This application relates to small molecule heterocyclic pharmaceuticals, and more particularly, to substituted pyridines and pyridazines having angiogenesis inhibiting activity.
Vasculogenesis involves the de novo formation of blood vessels from endothelial cell precursors or angioblasts. The first vascular structures in the embryo are formed by vasculogenesis. Angiogenesis involves the development of capillaries from existing blood vessels, and is the principle mechanism by which organs, such as the brain and the kidney are vascularized. While vasculogenesis is restricted to embryonic development, angiogenesis can occur in the adult, for example during pregnancy, the female cycle, or wound healing.
One major regulator of angiogenesis and vasculogenesis in both embryonic development and some angiogenic-dependent diseases is vascular endothelial growth factor (VEGF; also called vascular permeability factor, VPF). VEGF represents a family of mitogens isoforms resulting from alternative mRNA splicing and which exist in homodimeric forms. The VEGF KDR receptor is highly specific for vascular endothelial cells (for reviews, see: Farrara et al. Endocr. Rev. 1992, 13, 18; Neufield et al. FASEB J. 1999, 13, 9).
VEGF expression is induced by hypoxia (Shweiki et al. Nature 1992, 359, 843), as well as by a variety of cytokines and growth factors, such as interleukin-1, interleukin-6, epidermal growth factor and transforming growth factor-xcex1 and -xcex2.
To date VEGF and the VEGF family members have been reported to bind to one or more of three transmembrane receptor tyrosine kinases (Mustonen et al. J. Cell Biol., 1995, 129, 895), VEGF receptor-1 (also known as flt-1 (fms-like tyrosine kinase-1)); VEGFR-2 (also known as kinase insert domain containing receptor (KDR), the murine analogue of KDR being known as fetal liver kinase-1 (flk-1)); and VEGFR-3 (also known as flt-4). KDR and flt-1 have been shown to have different signal transduction properties (Waltenberger et al. J. Biol. Chem. 1994, 269, 26988); Park et al. Oncogene 1995, 10, 135). Thus, KDR undergoes strong ligand-dependent tyrosine phosphorylation in intact cells, whereas flt-1 displays a weaker response. Thus, binding to KDR is a critical requirement for induction of the full spectrum of VEGF-mediated biological responses.
In vivo, VEGF plays a central role in vasculogenesis, and induces angiogenesis and permeabilization of blood vessels. Deregulated VEGF expression contributes to the development of a number of diseases that are characterized by abnormal angiogenesis and/or hyperpermeability processes. Regulation of the VEGF-mediated signal transduction cascade will therefore provide a useful mode for control of abnormal angiogenesis and/or hyperpermeability processes.
Angiogenesis is regarded as an absolute prerequisite for growth of tumors beyond about 1-2 mm. Oxygen and nutrients may be supplied to cells in tumors smaller than this limit through diffusion. However, every tumor is dependent on angiogenesis for continued growth after it has reached a certain size. Tumorigenic cells within hypoxic regions of tumors respond by stimulation of VEGF production, which triggers activation of quiescent endothelial cells to stimulate new blood vessel formation. (Shweiki et al. Proc. Nat""l. Acad. Sci., 1995, 92, 768). In addition, VEGF production in tumor regions where there is no angiogenesis may proceed through the ras signal transduction pathway (Grugel et al. J. Biol. Chem., 1995, 270, 25915; Rak et al. Cancer Res. 1995, 55, 4575). In situ hybridization studies have demonstrated VEGF mRNA is strongly upregulated in a wide variety of human tumors, including lung (Mattern et al. Br. J. Cancer 1996, 73, 931), thyroid (Viglietto et al. Oncogene 1995, 11, 1569), breast (Brown et al. Human Pathol. 1995, 26, 86), gastrointestional tract (Brown et al. Cancer Res. 1993, 53, 4727; Suzuki et al. Cancer Res. 1996, 56, 3004), kidney and bladder (Brown et al. Am. J. Pathol. 1993, 143I, 1255), ovary (Olson et al. Cancer Res. 1994, 54, 1255), and cervical (Guidi et al. J. Nat""l Cancer Inst. 1995, 87, 12137) carcinomas, as well as angiosacroma (Hashimoto et al. Lab. Invest. 1995, 73, 859) and several intracranial tumors (Plate et al. Nature 1992, 359, 845; Phillips et al. Int. J. Oncol. 1993, 2, 913; Berkman et al. J. Clin. Invest., 1993, 91, 153). Neutralizing monoclonal antibodies to KDR have been shown to be efficacious in blocking tumor angiogenesis (Kim et al. Nature 1993, 362, 841; Rockwell et al. Mol. Cell. Differ. 1995, 3, 315).
Overexpression of VEGF, for example under conditions of extreme hypoxia, can lead to intraocular angiogenesis, resulting in hyperproliferation of blood vessels, leading eventually to blindness. Such a cascade of events has been observed for a number of retinopathies, including diabetic retinopathy, ischemic retinal-vein occlusion, retinopathy of prematurity (Aiello et al. New Engl. J. Med. 1994, 331, 1480; Peer et al. Lab. Invest. 1995, 72, 638), and age-related macular degeneration (AMD; see, Lopez et al. Invest. Opththalmol. Vis. Sci. 1996, 37, 855).
In rheumatoid arthritis (RA), the in-growth of vascular pannus may be mediated by production of angiogenic factors. Levels of immunoreactive VEGF are high in the synovial fluid of RA patients, while VEGF levels were low in the synovial fluid of patients with other forms of arthritis of with degenerative joint disease (Koch et al. J. Immunol. 1994, 152, 4149). The angiogenesis inhibitor AGM-170 has been shown to prevent neovascularization of the joint in the rat collagen arthritis model (Peacock et al. J. Exper. Med. 1992, 175, 1135).
Increased VEGF expression has also been shown in psoriatic skin, as well as bullous disorders associated with subepidermal blister formation, such as bullous pemphigoid, erythema multiforme, and dermatitis herpetiformis (Brown et al. J. Invest. Dermatol. 1995, 104, 744).
Because inhibition of KDR signal transduction leads to inhibition of VEGF-mediated angiogenesis and permeabilization, KDR inhibitors will be useful in treatment of diseases characterized by abnormal angiogenesis and/or hyperpermeability processes, including the above listed diseases.
Examples of phthalazines and other fused pyridazines that are similar in structure to those of the present application are disclosed in the following patents or patent applications: WO 9835958 (Novartis), U.S. Pat. Nos. 5,849,741, 3,753,988, 3,478,028 and JP 03106875. Other literature references to phthalazines are El-Feky, S. A., Bayoumy, B. E., and Abd El-Sami, Z. K., Egypt. J. Chem. (1991), Volume Date 1990, 33(2), 189-197; Duhault, J., Gonnard, P., and Fenard, S., Bull. Soc. Chim. Biol., (1967), 49 (2), 177-190; and Holava, H. M. and Jr, Partyka, R. A., J. Med. Chem., (1969), 12, 555-556. The compounds of the present invention are distinct from those described in each of the above references, and only the Novartis publication describes such compounds as inhibitors of angiogenesis.
As explained above, compounds which inhibit angiogenesis have applicability in treatment of a variety of medical conditions, and are therefore desirable. Such materials are the subject of the present application.
In its broadest aspect, the present invention relates to the sum of three sets of chemical compounds, or pharmaceutically acceptable salts or prodrugs thereof, with each set overlapping the others in scope. The generalized structural formula for the compounds in each of the three sets of compounds is the same, but it should be noted that the definitions of the several groups comprising the general structure in each set differ somewhat. Thus, the defined sets of chemical compounds differ from each other, but overlap in their scopes.
The first set of compounds have the generalized structural formula 
wherein
R1 and R2 together form a bridge containing two T2 moieties and one T3 moiety, said bridge, taken together with the ring to which it is attached, forming a bicyclic of structure 
xe2x80x83wherein
each T2 independently represents N, CH, or CG1;
T3 represents S, O, CR4G1, C(R4)2, or NR3.
In the above substructures, G1 is a substituent independently selected from the group consisting of xe2x80x94N(R6)2; xe2x80x94NR3COR6; halogen; alkyl; cycloalkyl; lower alkenyl; lower cycloalkenyl; halogen-substituted alkyl; amino-substituted alkyl; N-lower alkylamino-substituted alkyl; N,N-di-lower alkylamino-substituted alkyl; N-lower alkanoylamino-substituted alkyl; hydroxy-substituted alkyl; cyano-substituted alkyl; carboxy-substituted alkyl; lower alkoxycarbonyl-substituted alkyl; phenyl lower alkoxycarbonyl-substituted alkyl; halogen-substituted alkylamino; amino-substituted alkylamino; N-lower alkylamino-substituted alkylamino; N,N-di-lower alkylamino-substituted alkylamino; N-lower alkanoylamino-substituted alkylamino; hydroxy-substituted alkylamino; cyano-substituted alkylamino; carboxy-substituted alkylamino; lower alkoxycarbonyl-substituted alkylamino; phenyl-lower alkoxycarbonyl-substituted alkylamino; xe2x80x94OR6; xe2x80x94SR6; xe2x80x94S(O)R6; xe2x80x94S(O)2R6; halogenated lower alkoxy; halogenated lower alkylthio; halogenated lower alkylsulfonyl; xe2x80x94OCOR6; xe2x80x94COR6; xe2x80x94CO2R6; xe2x80x94CON(R6)2; xe2x80x94CH2OR3; xe2x80x94NO2; xe2x80x94CN; amidino guanidino; sulfo; xe2x80x94B(OH)2; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted saturated heterocyclyl; optionally substituted saturated heterocyclylalkyl; optionally substituted partially unsaturated heterocyclyl; optionally substituted partially unsaturated heterocyclylalkyl; xe2x80x94OCO2R3; optionally substituted heteroarylalkyl; optionally substituted heteroaryloxy; xe2x80x94S(O)p(optionally substituted heteroaryl); optionally substituted heteroarylalkyloxy; xe2x80x94S(O)p(optionally substituted heteroarylalkyl); xe2x80x94CHO; xe2x80x94OCON(R6)2; xe2x80x94NR3CO2R6; and xe2x80x94NR3CON(R6)2.
The group R3 is H or lower alkyl. R6 is independently selected from the group consisting of H; alkyl; cycloalkyl; optionally substituted aryl; optionally substituted aryl lower alkyl, lower alkyl-N(R3)2, and lower alkyl-OH.
In generalized structural formula (I), R4 is H, halogen, or lower alkyl. The subscript p is 0, 1, or 2; and X is selected from the group consisting of O, S, and NR3.
The linking moiety Y is selected from the group consisting of lower alkylene; xe2x80x94CH2xe2x80x94Oxe2x80x94; xe2x80x94CH2xe2x80x94Sxe2x80x94; xe2x80x94CH2xe2x80x94NHxe2x80x94; xe2x80x94Oxe2x80x94; xe2x80x94Sxe2x80x94; xe2x80x94NHxe2x80x94; xe2x80x94Oxe2x80x94CH2xe2x80x94; xe2x80x94S(O)xe2x80x94; xe2x80x94S(O)2xe2x80x94; xe2x80x94SCH2xe2x80x94; xe2x80x94S(O)CH2xe2x80x94; xe2x80x94S(O)2CH2xe2x80x94; xe2x80x94CH2S(O)xe2x80x94; xe2x80x94CH2S(O)2; xe2x80x94(CR42)nxe2x80x94S(O)p-(5-membered heteroaryl)-(CR42)sxe2x80x94; and xe2x80x94(CR42)nxe2x80x94C(G2)(R4)xe2x80x94(CR42)sxe2x80x94. In the latter two linking groups Y, n and s are each independently 0 or an integer of 1-2. The substituent G2 is selected from the group consisting of xe2x80x94CN, xe2x80x94CO2R3, xe2x80x94CON(R6)2, and xe2x80x94CH2N(R6)2.
Z represents CR4 or N.
Regarding the ring containing A, B, D, E, and L, the number of possible substituents G3 on the ring is indicated by subscript q, which is 0, 1, or 2.
Substituent moieties G3 are monovalent or bivalent moieties selected from the group consisting of: lower alkyl; xe2x80x94NR3COR6; carboxy-substituted alkyl; lower alkoxycarbonyl-substituted alkyl; xe2x80x94OR6; xe2x80x94SR6; xe2x80x94S(O)R6; xe2x80x94S(O)2R6; xe2x80x94OCOR6; xe2x80x94COR6; xe2x80x94CO2R6; xe2x80x94CH2OR3; xe2x80x94CON(R6)2; xe2x80x94S(O)2N(R6)2; xe2x80x94NO2; xe2x80x94CN; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted saturated heterocyclyl; optionally substituted partially unsaturated heterocyclyl; optionally substituted heteroarylalkyl; optionally substituted heteroaryloxy; xe2x80x94S(O)p(optionally substituted heteroaryl); optionally substituted heteroarylalkyloxy; xe2x80x94S(O)p(optionally substituted heteroarylalkyl); xe2x80x94OCON(R6)2; xe2x80x94NR3CO2R6; xe2x80x94NR3CON(R6)2; and bivalent bridge of structure T2xe2x95x90T2xe2x80x94T3. In this bivalent bridge, each T2 independently represents N, CH, or CG3xe2x80x2; and T3 represents S, O, CR4G3xe2x80x2, C(R4)2, or NR3. G3xe2x80x2 represents any of the above-defined moieties G3 which are monovalent; and the terminal T2 of the bridge is bound to L, and T3 is bound to D, thus forming a 5-membered fused ring.
In the ring shown at the left in generalized structural formula (I), A and D independently represent N or CH; B and E independently represent N or CH; and L represents N or CH; with the provisos that a) the total number of N atoms in the ring containing A, B, D, E, and L is 0, 1, 2, or 3; b) when L represents CH and any G3 is a monovalent substituent, at least one of A and D is an N atom; and c) when L represents CH and a G3 is a bivalent bridge of structure T2xe2x95x90T2xe2x80x94T3, then A, B, D, and E are also CH.
J is a ring selected from the group consisting of aryl; pyridyl; and cycloalkyl. The subscript qxe2x80x2 represents the number of substituents G4 on ring J and is 0, 1, 2, 3, 4, or 5.
The possible substituents G4 on ring J are monovalent or bivalent moieties selected from the group consisting of xe2x80x94N(R6)2; xe2x80x94NR3COR6; halogen; alkyl; cycloalkyl; lower alkenyl; lower cycloalkenyl; halogen-substituted alkyl; amino-substituted alkyl; N-lower alkylamino-substituted alkyl; N,N-di-lower alkylamino-substituted alkyl; N-lower alkanoylamino-substituted alkyl; hydroxy-substituted alkyl; cyano-substituted alkyl; carboxy-substituted alkyl; lower alkoxycarbonyl-substituted alkyl; phenyl lower alkoxycarbonyl-substituted alkyl; halogen-substituted alkylamino; amino-substituted alkylamino; N-lower alkylamino-substituted alkylamino; N,N-di-lower alkylamino-substituted alkylamino; N-lower alkanoylamino-substituted alkylamino; hydroxy-substituted alkylamino; cyano-substituted alkylamino; carboxy-substituted alkylamino; lower alkoxycarbonyl-substituted alkylamino; phenyl-lower alkoxycarbonyl-substituted alkylamino; xe2x80x94OR6; xe2x80x94SR6; xe2x80x94S(O)R6; xe2x80x94S(O)2R6; halogenated lower alkoxy; halogenated lower alkylthio; halogenated lower alkylsulfonyl; xe2x80x94OCOR6; xe2x80x94COR6; xe2x80x94CO2R6; xe2x80x94CON(R6)2; xe2x80x94CH2OR3; xe2x80x94NO2; xe2x80x94CN; amidino; guanidino; sulfo; xe2x80x94B(OH)2; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted saturated heterocyclyl; optionally substituted partially unsaturated heterocyclyl; xe2x80x94OCO2R3; optionally substituted heteroarylalkyl; optionally substituted heteroaryloxy; xe2x80x94S(O)p(optionally substituted heteroaryl); optionally substituted heteroarylalkyloxy; xe2x80x94S(O)p(optionally substituted heteroarylalkyl); xe2x80x94CHO; xe2x80x94OCON(R6)2; xe2x80x94NR3CO2R6; xe2x80x94NR3CON(R6)2; and fused ring-forming bivalent bridges attached to and connecting adjacent positions of ring J, said bridges having the structures: 
xe2x80x83wherein each T2 independently represents N, CH, or CG4xe2x80x2; T3 represents S, O, CR4G4xe2x80x2, C(R4)2, or NR3; G4xe2x80x2 represents any of the above-defined moieties G4 which are monovalent; and binding to ring J is achieved via terminal atoms T2 and T3; 
xe2x80x83wherein each T2 independently represents N, CH, or CG4xe2x80x2; G4xe2x80x2 represents any of the above-defined moieties G4 which are monovalent; with the proviso that a maximum of two bridge atoms T2 may be N; and binding to ring J is achieved via terminal atoms T2; and 
xe2x80x83wherein each T4, T5 and T6 independently represents O, S, CR4G4xe2x80x2, C(R4)2, or NR3; G4xe2x80x2 represents any of the above-defined moieties G4 which are monovalent; and binding to ring J is achieved via terminal atoms T4 or T5; with the provisos that:
i) when one T4 is O, S, or NR3, the other T4 is CR4G4xe2x80x2 or C(R4)2;
ii) a bridge comprising T5 and T6 atoms may contain a maximum of two heteroatoms O, S, or N; and
iii) in a bridge comprising T5 and T6 atoms, when one T5 group and one T6 group are O atoms, or two T6 groups are O atoms, said O atoms are separated by at least one carbon atom.
When G4 is an alkyl group located on ring J adjacent to the linkage xe2x80x94(CR42)pxe2x80x94, and X is NR3 wherein R3 is an alkyl substituent; then G4 and the alkyl substituent R3 on X may be joined to form a bridge of structure xe2x80x94(CH2)pxe2x80x2xe2x80x94 wherein pxe2x80x2 is 2, 3, or 4, with the proviso that the sum of p and pxe2x80x2 is 2, 3, or 4, resulting in formation of a nitrogen-containing ring of 5, 6, or 7 members.
Additional provisos are that: 1) in G1, G2, G3, and G4, when two groups R3 or R6 are each alkyl and located on the same N atom they may be linked by a bond, an O, an S, or NR3 to form a N-containing heterocycle of 5-7 ring atoms; and 2) when an aryl, heteroaryl, or heterocyclyl ring is optionally substituted, that ring may bear up to 5 substituents which are independently selected from the group consisting of amino, mono-loweralkyl-substituted amino, di-loweralkyl-substituted amino, lower alkanoylamino, halogeno, lower alkyl, halogenated lower alkyl, hydroxy, lower alkoxy, lower alkylthio, halogenated lower alkoxy, halogenated lower alkylthio, lower alkanoyloxy, xe2x80x94CO2R3, xe2x80x94CHO, xe2x80x94CH2OR3, xe2x80x94OCO2R3, xe2x80x94CON(R6)2, xe2x80x94OCON(R6)2, xe2x80x94NR3CON(R6)2, nitro, amidino, guanidino, mercapto, sulfo, and cyano; and 3) when any alkyl group is attached to O, S, or N, and bears a hydroxyl substituent, then said hydroxyl substituent is separated by at least two carbon atoms from the O, S, or N to which the alkyl group is attached.
The second set of compounds have the generalized structural formula 
wherein
R1 and R2:
i) independently represent H or lower alkyl;
ii) together form a bridge of structure 
xe2x80x83wherein binding is achieved via the terminal carbon atoms;
iii) together form a bridge of structure 
xe2x80x83wherein binding is achieved via the terminal carbon atoms;
iv) together form a bridge of structure 
xe2x80x83wherein one or two ring members T1 are N and the others are CH or CG1, and binding is achieved via the terminal atoms; or
v) together form a bridge containing two T2 moieties and one T3 moiety, said bridge, taken together with the ring to which it is attached, forming a bicyclic of structure 
xe2x80x83wherein
each T2 independently represents N, CH, or CG1;
T3 represents S, O, CR4G1, C(R4)2, or NR3.
In the above bridge substructures, the subscript m is 0 or an integer 1-4; indicating that the resultant fused rings may optionally bear up to four substituents G1.
G1 is a substituent independently selected from the group consisting of xe2x80x94N(R6)2; xe2x80x94NR3COR6; halogen; alkyl; cycloalkyl; lower alkenyl; lower cycloalkenyl; halogen-substituted alkyl; amino-substituted alkyl; N-lower alkylamino-substituted alkyl; N,N-di-lower alkylamino-substituted alkyl; N-lower alkanoylamino-substituted alkyl; hydroxy-substituted alkyl; cyano-substituted alkyl; carboxy-substituted alkyl; lower alkoxycarbonyl-substituted alkyl; phenyl lower alkoxycarbonyl-substituted alkyl; halogen-substituted alkylamino; amino-substituted alkylamino; N-lower alkylamino-substituted alkylamino; N,N-di-lower alkylamino-substituted alkylamino; N-lower alkanoylamino-substituted alkylamino; hydroxy-substituted alkylamino; cyano-substituted alkylamino; carboxy-substituted alkylamino; lower alkoxycarbonyl-substituted alkylamino; phenyl-lower alkoxycarbonyl-substituted alkylamino; xe2x80x94OR6; xe2x80x94SR6; xe2x80x94S(O)R6; xe2x80x94S(O)2R6; halogenated lower alkoxy; halogenated lower alkylthio; halogenated lower alkylsulfonyl; xe2x80x94OCOR6; xe2x80x94COR6; xe2x80x94CO2R6; xe2x80x94CON(R6)2; xe2x80x94CH2OR3; xe2x80x94NO2; xe2x80x94CN; amidino; guanidino; sulfo; xe2x80x94B(OH)2; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted saturated heterocyclyl; optionally substituted saturated heterocyclylalkyl; optionally substituted partially unsaturated heterocyclyl; optionally substituted partially unsaturated heterocyclylalkyl; xe2x80x94OCO2R3; optionally substituted heteroarylalkyl; optionally substituted heteroaryloxy; xe2x80x94S(O)p(optionally substituted heteroaryl); optionally substituted heteroarylalkyloxy; xe2x80x94S(O)p(optionally substituted heteroarylalkyl); xe2x80x94CHO; xe2x80x94OCON(R6)2; xe2x80x94NR3CO2R6; and xe2x80x94NR3CON(R6)2.
The group R3 is H or lower alkyl. R6 is independently selected from the group consisting of H; alkyl; cycloalkyl; optionally substituted aryl; optionally substituted aryl lower alkyl; lower alkyl-N(R3)2, and lower alkyl-OH.
In generalized structural formula (I), R4 is H, halogen, or lower alkyl; the subscript p is 0, 1, or 2; and X is selected from the group consisting of O, S, and NR3.
The linking moiety Y is selected from the group consisting of lower alkylene; xe2x80x94CH2Oxe2x80x94; xe2x80x94CH2xe2x80x94Sxe2x80x94; xe2x80x94CH2xe2x80x94NHxe2x80x94; xe2x80x94Oxe2x80x94; xe2x80x94Sxe2x80x94; xe2x80x94NHxe2x80x94; xe2x80x94Oxe2x80x94CH2xe2x80x94; xe2x80x94S(O)xe2x80x94; xe2x80x94S(O)2xe2x80x94; xe2x80x94SCH2xe2x80x94; xe2x80x94S(O)CH2xe2x80x94; xe2x80x94S(O)2CH2xe2x80x94; xe2x80x94CH2S(O)xe2x80x94; xe2x80x94CH2S(O)2xe2x80x94; xe2x80x94(CR42)nxe2x80x94S(O)pxe2x80x94(5-membered heteroaryl)-(CR42)sxe2x80x94; and xe2x80x94(CR42)nxe2x80x94C(G2)(R4)xe2x80x94(CR42)sxe2x80x94. In the latter two linking groups Y, subscripts n and s are each independently 0 or an integer of 1-2. G2 is selected from the group consisting of xe2x80x94CN, xe2x80x94CO2R3, xe2x80x94CON(R6)2, and xe2x80x94CH2N(R6)2.
Z represents N or CR4.
Regarding the ring containing A, B, D, E, and L, the number of possible substituents G3 on the ring is indicated by the subscript q, which is 1 or 2.
Substituents G3 are monovalent or bivalent moieties selected from the group consisting of lower alkyl; xe2x80x94NR3COR6; carboxy-substituted alkyl; lower alkoxycarbonyl-substituted alkyl; xe2x80x94OR6; xe2x80x94SR6; xe2x80x94S(O)R6; xe2x80x94S(O)2R6; xe2x80x94OCOR6; xe2x80x94COR6; xe2x80x94CO2R6; xe2x80x94CH2OR3; xe2x80x94CON(R6)2; xe2x80x94S(O)2N(R6)2; xe2x80x94NO2; xe2x80x94CN; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted saturated heterocyclyl; optionally substituted partially unsaturated heterocyclyl; optionally substituted heteroarylalkyl; optionally substituted heteroaryloxy; xe2x80x94S(O)p(optionally substituted heteroaryl); optionally substituted heteroarylalkyloxy; xe2x80x94S(O)p(optionally substituted heteroarylalkyl); xe2x80x94OCON(R6)2; xe2x80x94NR3CO2R6; xe2x80x94NR3CON(R6)2; and bivalent bridge of structure T2xe2x95x90T2xe2x80x94T3. In this bivalent bridge, each T2 independently represents N, CH, or CG3xe2x80x2; and T3 represents S, O, CR4G3xe2x80x2, C(R4)2, or NR3. G3 represents any of the above-defined moieties G3 which are monovalent; and the terminal T2 is bound to L, and T3 is bound to D, thus forming a 5-membered fused ring.
In the ring shown at the left in generalized structural formula (I), A and D independently represent CH; B and E independently represent CH; and L is CH; with the proviso that the resulting phenyl ring bears as a G3 substituent said bivalent bridge of structure T2xe2x95x90T2xe2x80x94T3.
J is a ring selected from the group consisting of aryl; pyridyl; and cycloalkyl. The subscript qxe2x80x2 represents the number of substituents G4 on ring J and is 0, 1, 2, 3, 4, or 5.
G4 is a monovalent or bivalent moiety selected from the group consisting of xe2x80x94N(R6)2; xe2x80x94NR3COR6; halogen; alkyl; cycloalkyl; lower alkenyl; lower cycloalkenyl; halogen-substituted alkyl; amino-substituted alkyl; N-lower alkylamino-substituted alkyl; N,N-di-lower alkylamino-substituted alkyl; N-lower alkanoylamino-substituted alkyl; hydroxy-substituted alkyl; cyano-substituted alkyl; carboxy-substituted alkyl; lower alkoxycarbonyl-substituted alkyl; phenyl lower alkoxycarbonyl-substituted alkyl; halogen-substituted alkylamino; amino-substituted alkylamino; N-lower alkylamino-substituted alkylamino; N,N-di-lower alkylamino-substituted alkylamino; N-lower alkanoylamino-substituted alkylamino; hydroxy-substituted alkylamino; cyano-substituted alkylamino; carboxy-substituted alkylamino; lower alkoxycarbonyl-substituted alkylamino; phenyl-lower alkoxycarbonyl-substituted alkylamino; xe2x80x94OR6; xe2x80x94SR6; xe2x80x94S(O)R6; xe2x80x94S(O)2R6; halogenated lower alkoxy; halogenated lower alkylthio; halogenated lower alkylsulfonyl; xe2x80x94OCOR6; xe2x80x94COR6; xe2x80x94CO2R6; xe2x80x94CON(R6)2; xe2x80x94CH2OR3; xe2x80x94NO2; xe2x80x94CN; amidino; guanidino; sulfo; xe2x80x94B(OH)2; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted saturated heterocyclyl; optionally substituted partially unsaturated heterocyclyl; xe2x80x94OCO2R3; optionally substituted heteroarylalkyl; optionally substituted heteroaryloxy; xe2x80x94S(O)p(optionally substituted heteroaryl); optionally substituted heteroarylalkyloxy; xe2x80x94S(O)p(optionally substituted heteroarylalkyl); xe2x80x94CHO; xe2x80x94OCON(R6)2; xe2x80x94NR3CO2R6; xe2x80x94NR3CON(R6)2; and fused ring-forming bivalent bridges attached to and connecting adjacent positions of ring J, said bridges having the structures: 
xe2x80x83wherein each T2 independently represents N, CH, or CG4xe2x80x2; T3 represents S, O, CR4G4xe2x80x2, C(R4)2, or NR3; G4xe2x80x2 represents any of the above-defined moieties G4 which are monovalent; and binding to ring J is achieved via terminal atoms T2 and T3; 
xe2x80x83wherein each T2 independently represents N, CH, or CG4xe2x80x2; G4xe2x80x2 represents any of the above-defined moieties G4 which are monovalent; with the proviso that a maximum of two bridge atoms T2 may be N; and binding to ring J is achieved via terminal atoms T2; and 
xe2x80x83wherein each T4, T5, and T6 independently represents O, S, CR4G4xe2x80x2, C(R4)2, or NR3; G4xe2x80x2 represents any of the above-identified moieties G4 which are monovalent; and binding to ring J is achieved via terminal atoms T4 or T5; with the provisos that:
i) when one T4 is O, S, or NR3, the other T4 is CR4G4xe2x80x2 or C(R4)2;
ii) a bridge comprising T5 and T6 atoms may contain a maximum of two heteroatoms O, S, or N; and
iii) in a bridge comprising T5 and T6 atoms, when one T5 group and one T6 group are O atoms, or two T6 groups are O atoms, said O atoms are separated by at least one carbon atom.
When G4 is an alkyl group located on ring J adjacent to the linkage xe2x80x94CR42)pxe2x80x94, and X is NR3 wherein R3 is an alkyl substituent, then G4 and the alkyl substituent R3 on X may be joined to form a bridge of structure xe2x80x94(CH2)pxe2x80x2xe2x80x94 wherein pxe2x80x2 is 2, 3, or 4, with the proviso that the sum of p and pxe2x80x2 is 2, 3, or 4, resulting in formation of a nitrogen-containing ring of 5, 6, or 7 members.
Additional provisos are that: 1) in G1, G2, G3, and G4, when two groups R3 or R6 are each alkyl and located on the same N atom they may be linked by a bond, an O, an S, or NR3 to form a N-containing heterocycle of 5-7 ring atoms; and 2) when an aryl, heteroaryl, or heterocyclyl ring is optionally substituted, that ring may bear up to 5 substituents which are independently selected from the group consisting of amino, mono-loweralkyl-substituted amino, di-loweralkyl-substituted amino, lower alkanoylamino, halogeno, lower alkyl, halogenated lower alkyl, hydroxy, lower alkoxy, lower alkylthio, halogenated lower alkoxy, halogenated lower alkylthio, lower alkanoyloxy, xe2x80x94CO2R3, xe2x80x94CHO, xe2x80x94CH2OR3, xe2x80x94OCO2R3, xe2x80x94CON(R6)2, xe2x80x94OCON(R6)2, xe2x80x94NR3CON(R6)2, nitro, amidino, guanidino, mercapto, sulfo, and cyano; and 3) when any alkyl group is attached to O, S, or N, and bears a hydroxyl substituent, then said hydroxyl substituent is separated by at least two carbon atoms from the O, S, or N to which the alkyl group is attached.
The third set of compounds have the generalized structural formula 
wherein
R1 and R2:
i) independently represent H or lower alkyl;
ii) together form a bridge of structure 
xe2x80x83wherein binding is achieved via the terminal carbon atoms;
iii) together form a bridge of structure 
xe2x80x83wherein binding is achieved via the terminal carbon atoms;
iv) together form a bridge of structure 
xe2x80x83wherein one or two ring members T1 are N and the others are CH or CG1, and binding is achieved via the terminal atoms; or
v) together form a bridge containing two T2 moieties and one T3 moiety, said bridge, taken together with the ring to which it is attached, forming a bicyclic of structure 
xe2x80x83wherein
each T2 independently represents N, CH, or CG1;
T3 represents S, O, CR4G1, C(R4)2, or NR3.
In the above bridge structures, the subscript m is 0 or an integer 1-4; indicating that the resultant fused rings may optionally bear up to four substituents G1.
G1 is a substituent independently selected from the group consisting of xe2x80x94N(R6)2; xe2x80x94NR3COR6; halogen; alkyl; cycloalkyl; lower alkenyl; lower cycloalkenyl; halogen-substituted alkyl; amino-substituted alkyl; N-lower alkylamino-substituted alkyl; N,N-di-lower alkylamino-substituted alkyl; N-lower alkanoylamino-substituted alkyl; hydroxy-substituted alkyl; cyano-substituted alkyl; carboxy-substituted alkyl; lower alkoxycarbonyl-substituted alkyl; phenyl lower alkoxycarbonyl-substituted alkyl; halogen-substituted alkylamino; amino-substituted alkylamino; N-lower alkylamino-substituted alkylamino; N,N-di-lower alkylamino-substituted alkylamino; N-lower alkanoylamino-substituted alkylamino; hydroxy-substituted alkylamino; cyano-substituted alkylamino; carboxy-substituted alkylamino; lower alkoxycarbonyl-substituted alkylamino; phenyl-lower alkoxycarbonyl-substituted alkylamino; xe2x80x94OR6; xe2x80x94SR6; xe2x80x94S(O)R6; xe2x80x94S(O)2R6; halogenated lower alkoxy; halogenated lower alkylthio; halogenated lower alkylsulfonyl; xe2x80x94OCOR6; xe2x80x94COR6; xe2x80x94CO2R6; xe2x80x94CON(R6)2; xe2x80x94CH2OR3; xe2x80x94NO2; xe2x80x94CN; amidino; guanidino; sulfo; xe2x80x94B(OH)2; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted saturated heterocyclyl; optionally substituted saturated heterocyclylalkyl; optionally substituted partially unsaturated heterocyclyl; optionally substituted partially unsaturated heterocyclylalkyl; xe2x80x94OCO2R3; optionally substituted heteroarylalkyl; optionally substituted heteroaryloxy; xe2x80x94S(O)p(optionally substituted heteroaryl); optionally substituted heteroarylalkyloxy; xe2x80x94S(O)p(optionally substituted heteroarylalkyl); xe2x80x94CHO; xe2x80x94OCON(R6)2; xe2x80x94NR3CO2R6; and xe2x80x94NR3CON(R6)2.
The group R3 is H or lower alkyl. R6 is independently selected from the group consisting of H; alkyl; cycloalkyl; optionally substituted aryl; optionally substituted aryl lower alkyl; lower alkyl-N(R3)2, and lower alkyl-OH.
In generalized structural formula (I), R4 is H, halogen, or lower alkyl; the subscript p is 0, 1, or 2; and X is selected from the group consisting of O, S, and NR3.
The linking moiety Y is selected from the group consisting of lower alkylene; xe2x80x94CH2Oxe2x80x94; xe2x80x94CH2xe2x80x94Sxe2x80x94; xe2x80x94CH2xe2x80x94NHxe2x80x94; xe2x80x94Oxe2x80x94; xe2x80x94Sxe2x80x94; xe2x80x94NHxe2x80x94; xe2x80x94Oxe2x80x94CH2xe2x80x94; xe2x80x94S(O)xe2x80x94; xe2x80x94S(O)2xe2x80x94; xe2x80x94SCH2xe2x80x94; xe2x80x94S(O)CH2xe2x80x94; xe2x80x94S(O)2CH2xe2x80x94; xe2x80x94CH2S(O)xe2x80x94; xe2x80x94CH2S(O)2xe2x80x94; xe2x80x94(CR42)nxe2x80x94S(O)pxe2x80x94(5-membered heteroaryl)-(CR42)sxe2x80x94; and xe2x80x94(CR42)nxe2x80x94C(G2)(R4)xe2x80x94(CR42)sxe2x80x94. In the latter two linking groups Y, subscripts n and s are each independently 0 or an integer of 1-2. G2 is selected from the group consisting of xe2x80x94CN, xe2x80x94CO2R3, xe2x80x94CON(R6)2, and xe2x80x94CH2N(R6)2.
Z represents CR4.
Regarding the ring containing A, B, D, E, and L, the number of possible substituents G3 on the ring is indicated by the subscript q, which is 1 or 2.
Substituents G are monovalent or bivalent moieties selected from the group consisting of xe2x80x94NR3COR6; carboxy-substituted alkyl; lower alkoxycarbonyl-substituted alkyl; xe2x80x94OR6; xe2x80x94SR6; xe2x80x94S(O)R6; xe2x80x94S(O)2R6; xe2x80x94OCOR6; xe2x80x94COR6; xe2x80x94CO2R6; xe2x80x94CH2OR3; xe2x80x94CON(R6)2; xe2x80x94S(O)2N(R6)2; xe2x80x94NO2; xe2x80x94CN; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted saturated heterocyclyl; optionally substituted partially unsaturated heterocyclyl; optionally substituted heteroarylalkyl; optionally substituted heteroaryloxy; xe2x80x94S(O)p(optionally substituted heteroaryl); optionally substituted heteroarylalkyloxy; xe2x80x94S(O)p(optionally substituted heteroarylalkyl); xe2x80x94OCON(R6)2; xe2x80x94NR3CO2R6; xe2x80x94NR3CON(R6)2; and bivalent bridge of structure T2xe2x95x90T2xe2x80x94T3. In this bivalent bridge, each T2 independently represents N, CH, or CG3xe2x80x2; and T3 represents S, O, CR4G3xe2x80x2, C(R4)2, or NR3. G3xe2x80x2 represents any of the above-defined moieties G3 which are monovalent; and the terminal T2 is bound to L, and T3 is bound to D, thus forming a 5-membered fused ring.
In the ring shown at the left in generalized structural formula (I), A and D independently represent N or CH; B and E independently represent N or CH; and L represents N or CH; with the provisos that a) the total number of N atoms in the ring containing A, B, D, E, and L is 0, 1, 2, or 3; and b) when L represents CH and any G3 is a monovalent substituent, at least one of A and D is an N atom; and c) when L represents CH and a G3 is a bivalent bridge of structure T2xe2x95x90T2xe2x80x94T3, then A, B, D, and E are also CH.
J is a ring selected from the group consisting of aryl; pyridyl; and cycloalkyl. The subscript qxe2x80x2 represents the number of substituents G4 on ring J and is 0, 1, 2, 3, 4, or 5.
G4 is a monovalent or bivalent moiety selected from the group consisting of xe2x80x94N(R6)2; xe2x80x94NR3COR6; halogen; alkyl; cycloalkyl; lower alkenyl; lower cycloalkenyl; halogen-substituted alkyl; amino-substituted alkyl; N-lower alkylamino-substituted alkyl; N,N-di-lower alkylamino-substituted alkyl; N-lower alkanoylamino-substituted alkyl; hydroxy-substituted alkyl; cyano-substituted alkyl; carboxy-substituted alkyl; lower alkoxycarbonyl-substituted alkyl; phenyl lower alkoxycarbonyl-substituted alkyl; halogen-substituted alkylamino; amino-substituted alkylamino; N-lower alkylamino-substituted alkylamino; N,N-di-lower alkylamino-substituted alkylamino; N-lower alkanoylamino-substituted alkylamino; hydroxy-substituted alkylamino; cyano-substituted alkylamino; carboxy-substituted alkylamino; lower alkoxycarbonyl-substituted alkylamino; phenyl-lower alkoxycarbonyl-substituted alkylamino; xe2x80x94OR6; xe2x80x94SR6; xe2x80x94S(O)R6; xe2x80x94S(O)2R6; halogenated lower alkoxy; halogenated lower alkylthio; halogenated lower alkylsulfonyl; xe2x80x94OCOR6; xe2x80x94COR6; xe2x80x94CO2R6; xe2x80x94CON(R6)2; xe2x80x94CH2OR3; xe2x80x94NO2; xe2x80x94CN; amidino; guanidino; sulfo; xe2x80x94B(OH)2; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted saturated heterocyclyl; optionally substituted partially unsaturated heterocyclyl; xe2x80x94OCO2R3; optionally substituted heteroarylalkyl; optionally substituted heteroaryloxy; xe2x80x94S(O)p(optionally substituted heteroaryl); optionally substituted heteroarylalkyloxy; xe2x80x94S(O)p(optionally substituted heteroarylalkyl); xe2x80x94CHO; xe2x80x94OCON(R6)2; xe2x80x94NR3CO2R6; xe2x80x94NR3CON(R6)2; and fused ring-forming bivalent bridges attached to and connecting adjacent positions of ring J, said bridges having the structures: 
xe2x80x83wherein each T2 independently represents N, CH, or CG4xe2x80x2; T3 represents S, O, CR4G4xe2x80x2, C(R4)2, or NR3; G4xe2x80x2 represents any of the above-defined moieties G4 which are monovalent; and binding to ring J is achieved via terminal atoms T2 and T3; 
xe2x80x83wherein each T2 independently represents N, CH, or CG4xe2x80x2; G4xe2x80x2 represents any of the above-defined moieties G4 which are monovalent; with the proviso that a maximum of two bridge atoms T2 may be N; and binding to ring J is achieved via terminal atoms T2; and 
xe2x80x83wherein each T4, T5, and T6 independently represents O, S, CR4G4xe2x80x2, C(R4)2, or NR3; G4xe2x80x2 represents any of the above-defined moieties G4 which are monovalent; and binding to ring J is achieved via terminal atoms T4 or T 5; with the provisos that:
i) when one T4 is O, S, or NR3, the other T is CR4G4xe2x80x2 or C(R4)2;
ii) a bridge comprising T5 and T6 atoms may contain a maximum of two heteroatoms O, S, or N; and
iii) in a bridge comprising T5 and T6 atoms, when one T5 group and one T6 group are O atoms, or two T6 groups are O atoms, said O atoms are separated by at least one carbon atom;
When G4 is an alkyl group located on ring J adjacent to the linkage xe2x80x94(CR42)pxe2x80x94, and X is NR3 wherein R3 is an alkyl substituent, then G4 and the alkyl substituent R3 on X may be joined to form a bridge of structure xe2x80x94(CH2)pxe2x80x2xe2x80x94 wherein pxe2x80x2 is 2, 3, or 4, with the proviso that the sum of p and pxe2x80x2 is 2, 3, or 4, resulting in formation of a nitrogen-containing ring of 5, 6, or 7 members.
Additional provisos are that: 1) in G1, G2, G3, and G4, when two groups R3 or R6 are each alkyl and located on the same N atom they may be linked by a bond, an O, an S, or NR3 to form a N-containing heterocycle of 5-7 ring atoms; and 2) when an aryl, heteroaryl, or heterocyclyl ring is optionally substituted, that ring may bear up to 5 substituents which are independently selected from the group consisting of amino, mono-loweralkyl-substituted amino, di-loweralkyl-substituted amino, lower alkanoylamino, halogeno, lower alkyl, halogenated lower alkyl, hydroxy, lower alkoxy, lower alkylthio, halogenated lower alkoxy, halogenated lower alkylthio, lower alkanoyloxy, xe2x80x94CO2R3, xe2x80x94CHO, xe2x80x94CH2OR3, xe2x80x94OCO2R3, xe2x80x94CON(R6)2, xe2x80x94OCON(R6)2, xe2x80x94NR3CON(R6)2, nitro, amidino, guanidino, mercapto, sulfo, and cyano; and 3) when any alkyl group is attached to O, S, or N, and bears a hydroxyl substituent, then said hydroxyl substituent is separated by at least two carbon atoms from the O, S, or N to which the alkyl group is attached.
Pharmaceutically acceptable salts of these compounds as well as commonly used prodrugs of these compounds such as O-acyl derivatives of invention compounds which contain hydroxy groups are also within the scope of the invention.
The invention also relates to pharmaceutical compositions comprising one or more of the compounds of the invention, or their salts or prodrugs, in a pharmaceutically acceptable carrier.
The invention also relates to a method for using these materials to treat a mammal having a condition characterized by abnormal angiogenesis or hyperpermiability processes, comprising administering to the mammal an amount of a compound of the invention, or a salt or prodrug thereof, which is effective to treat the condition.
The prefix xe2x80x9clowerxe2x80x9d denotes a radical having up to and including a maximum of 7 atoms, especially up to and including a maximum of 5 carbon atoms, the radicals in question being either linear or branched with single or multiple branching.
xe2x80x9cAlkylxe2x80x9d means a hydrocarbon radical having up to a maximum of 12 carbon atoms, which may be linear or branched with single or multiple branching. Alkyl is especially lower alkyl.
Where the plural form is used for compounds, salts, and the like, this is taken to mean also a single compound, salt, or the like.
Any asymmetric carbon atoms may be present in the (R)-, (S)- or (R,S)configuration, preferably in the (R)- or (S)-configuration. Substituents at a double bond or a ring may be present in cis- (xe2x95x90Z-) or trans (xe2x95x90E-) form. The compounds may thus be present as mixtures of isomers or as pure isomers, preferably as enantiomer-pure diastereomers and having pure cis- or trans-double bonds.
Lower alkylene Y may be branched or linear but is preferably linear, especially methylene (xe2x80x94CH2), ethylene (xe2x80x94CH2xe2x80x94CH2), trimethylene (xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2) or tetramethylene (xe2x80x94CH2CH2CH2CH2). When Y is lower alkylene, it is most preferably methylene.
xe2x80x9cArylxe2x80x9d means an aromatic radical having 6 to 14 carbon atoms, such as phenyl, naphthyl, fluorenyl or phenanthrenyl.
xe2x80x9cHalogenxe2x80x9d means fluorine, chlorine, bromine, or iodine but is especially fluorine, chlorine, or bromine.
xe2x80x9cPyridylxe2x80x9d means 1-, 2-, or 3-pyridyl but is especially 2- or 3-pyridyl.
xe2x80x9cCycloalkylxe2x80x9d is a saturated carbocycle that contains between 3 and 12 carbons but preferably 3 to 8 carbons.
xe2x80x9cCycloalkenylxe2x80x9d means a non-reactive and non-aromatic unsaturated carbocycle that contains between 3 and 12 carbons but preferably 3 to 8 carbons and up to three double bonds. It is well known to those skilled in the art that cycloalkenyl groups that differ from aromatics by lacking only one double bond such as cyclohaxadiene are not sufficiently non-reactive to be reasonable drug substances and therefor their use as substituents is not within the scope of this invention.
Cycloalkyl and cycloalkenyl groups may contain branch points such that they are substituted by alkyl or alkenyl groups. Examples of such branched cyclic groups are 3,4-dimethylcyclopentyl, 4-allylcyclohexyl or 3-ethylcyclopent-3-enyl.
Salts are especially the pharmaceutically acceptable salts of compounds of formula I such as, for example, acid addition salts, preferably with organic or inorganic acids, from compounds of formula I with a basic nitrogen atom. Suitable inorganic acids are, for example, halogen acids such as hydrochloric acid, sulfuric acid, or phosphoric acid. Suitable organic acids are, for example, carboxylic, phosphonic, sulfonic, or sulfamic acids, for example acetic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, -hydroxybutyric acid, gluconic acid, glucosemonocarboxylic acid, fumaric acid, succinic acid, adipic acid, pimelic acid, suberic acid, azeiaic acid, malic acid, tartaric acid, citric acid, glucaric acid, galactaric acid, amino acids, such as glutamic acid, aspartic acid, N-methylglycine, acetytaminoacetic acid, N-acetylasparagine or N-acetylcysteine, pyruvic acid, acetoacetic acid, phosphoserine, 2- or 3-glycerophosphoric acid.
In the definition of Y, the diradical xe2x80x9c-(5 member heteroaryl)-xe2x80x9d denotes a 5-membered aromatic heterocycle containing 1-3 heteroatoms selected from O, S, and N, the number of N atoms being 0-3 and the number of O and S atoms each being 0-1 and connected to the sulfur from a carbon and to xe2x80x94(CR42)sxe2x80x94 through a C or N atom. Examples of such diradicals include 
In the definitions of G1, G2, G3, and G4 the statement is made that when two groups R3 or R6 are found on a single N, they can be combined into a heterocycle of 5-7 atoms. Examples of such heterocycles, including the N to which they are attached, are: 
xe2x80x9cHeterocyclylxe2x80x9d or xe2x80x9cheterocyclexe2x80x9d means a five- to seven-membered heterocyclic system with 1-3 heteroatoms selected from the group nitrogen, oxygen, and sulfur, which may be unsaturated or wholly or partly saturated, and is unsubstituted or substituted especially by lower alkyl, such as methyl, ethyl, 1-propyl, 2-propyl, or tert-butyl.
When an aryl, heteroaryl, or heterocyclyl ring is said to be optionally substituted, that ring may bear up to 5 substituents which are independently selected from the group consisting of amino, mono- or di-loweralkyl-substituted amino, lower alkanoylamino, halogeno, lower alkyl, halogenated lower alkyl such as trifluoromethyl, hydroxy, lower alkoxy, lower alkylthio, halogenated lower alkoxy such as trifluoromethoxy, halogenated lower alkylthio such as trifluoromethylthio, lower alkanoyloxy, xe2x80x94CO2R3, xe2x80x94CHO, xe2x80x94CH2OR3, xe2x80x94OCO2R3, xe2x80x94CON(R6)2, xe2x80x94OCON(R6)2, xe2x80x94NR3CON(R6)2, nitro, amidino, guanidino, mercapto, sulfo, and cyano.
In the ring attached to Y, the ring members A, B, D, E, and L may be N or CH, it being understood that the optional substituents G3 are necessarily attached to carbon and not nitrogen, and that when a given carbon bears a substituent group G3, that G3 group is in place of the H atom the carbon would bear in the absence of the G3 group.
Examples of ring J together with two adjacent G4 moieties which taken together form a second fused ring are: 
xe2x80x9cHeteroarylxe2x80x9d means a monocyclic or fused bicyclic aromatic system with between 5 and 10 atoms in total of which 1-4 are heteroatoms selected from the group comprising nitrogen, oxygen, and sulfur and with the remainder being carbon. Heteroaryl is preferably a monocyclic system with 5 or 6 atoms in total, of which 1-3 are heteroatoms.
xe2x80x9cAlkenylxe2x80x9d means an unsaturated radical having up to a maximum of 12 carbon atoms and may be linear or branched with single or multiple branching and containing up to 3 double bonds. Alkenyl is especially lower alkenyl with up to 2 double bonds.
xe2x80x9cAlkanoylxe2x80x9d means alkylcarbonyl, and is especially lower alkylcarbonyl.
Halogenated lower alkyl, halogenated lower alkoxy and halogenated lower alkylthio are substituents in which the alkyl moieties are substituted either partially or in full with halogens, preferably with chlorine and/or fluorine and most preferably with fluorine. Examples of such substituents are trifluoromethyl, trifluoromethoxy, trifluoromethylthio, 1,1,2,2-tetrafluoroethoxy, dichloromethyl, fluoromethyl and difluoromethyl.
When a substituent is named as a string of fragments such as xe2x80x9cphenyl-lower alkoxycarbonyl-substituted alkylaminoxe2x80x9d, it is understood that the point of attachment is to the final moiety of that string (in this case amino) and that the other fragments of that string are connected to each other in sequence as they are listed in the string. Thus an example of xe2x80x9cphenyl-lower alkoxycarbonyl-substituted alkylaminoxe2x80x9d is: 
When a substituent is named as a string of fragments with a bond at the start (typically written as a dash) such as xe2x80x9cxe2x80x94S(O)p(optionally substituted heteroarylalkyl)xe2x80x9d, it is understood that the point of attachment is to the first atom of that string (in this case S or sulfur) and that the other fragments of that string are connected to each other in sequence as they are listed in the string. Thus an example of xe2x80x9cxe2x80x94S(O)p(optionally substituted heteroarylalkyl)xe2x80x9d is: 
It is to be understood that the left-most moiety of each of the variants of the linker Y is connected to the ring containing A, B, D, E, and L and that the right-most moiety of the linker is connected to the pyridazine fragment of the generalized formulae. Thus, examples of the use of the linker xe2x80x9cxe2x80x94CH2xe2x80x94Oxe2x80x94xe2x80x9d or of the linker xe2x80x9cxe2x80x94Oxe2x80x94CH2xe2x80x94xe2x80x9d are represented in the following invention compounds: 
In generalized structural formula (I), the preferred and most preferred groups are as follows.
R1 and R2 preferably:
i) together form a bridge of structure 
xe2x80x83wherein binding is achieved via the terminal carbon atoms; or
ii) together form a bridge of structure 
xe2x80x83wherein one of the ring members T1 is N and the others are CH, and binding is achieved via the terminal atoms; or
iii) together form a bridge containing two T2 moieties and one T3 moiety, said bridge, taken together with the ring to which it is attached, forming a bicyclic of structure 
xe2x80x83wherein
each T2 independently represents N, CH, or CG1;
T3 represents S, O, CH2, or NR3; and
with the proviso that when T3 is O or S, at least one T2 is CH or CG1.
Most preferably, any group G1 is located on a non-terminal atom of the bridge. Most preferably, in the bridge in iii), the terminal T2 is N or CH, the non-terminal T2 is CH or CG1, and T3 is S or O.
The subscript m is preferably 0 or an integer 1-2, and substituents G1 are preferably selected from the group consisting of xe2x80x94N(R6)2; xe2x80x94NR3COR6; halogen; lower alkyl; hydroxy-substituted alkyl; amino-substituted alkylamino; N-lower alkylamino-substituted alkylamino; N,N-di-lower alkylamino-substituted alkylamino; hydroxy-substituted alkylamino; carboxy-substituted alkylamino; lower alkoxycarbonyl-substituted alkylamino; xe2x80x94OR6; xe2x80x94SR6; xe2x80x94S(O)R6; xe2x80x94S(O)2R6; halogenated lower alkoxy; halogenated lower alkylthio; halogenated lower alkylsulfonyl; xe2x80x94OCOR6; xe2x80x94COR6; xe2x80x94CO2R6; xe2x80x94CON(R6)2; xe2x80x94NO2; xe2x80x94CN; optionally substituted heteroarylalkyl; optionally substituted heteroaryloxy; optionally substituted heteroarylalkyloxy; and xe2x80x94S(O)p(optionally substituted heteroarylalkyl). Most preferably, m is 0, and G1 is a substituent independently selected from the group consisting of xe2x80x94N(R6)2; xe2x80x94NR3COR6; halogen; xe2x80x94OR6 wherein R6 represents lower alkyl; xe2x80x94NO2; optionally substituted heteroaryloxy; and optionally substituted heteroarylalkyloxy.
When R6 is an alkyl group, it is preferably lower alkyl. The group R4 is preferably H; p is preferably 0 or 1; and X is preferably NR3.
In the linker group Y, the subscripts n and s are preferably 0 or 1, most preferably 0. Preferably, Y is selected from the group consisting of lower alkylene, xe2x80x94CH2xe2x80x94Oxe2x80x94; xe2x80x94CH2xe2x80x94Sxe2x80x94; xe2x80x94CH2xe2x80x94NHxe2x80x94; xe2x80x94Sxe2x80x94; xe2x80x94NHxe2x80x94; xe2x80x94(CR42)nxe2x80x94S(O)pxe2x80x94(5-membered heteroaryl)-(CR42)sxe2x80x94; xe2x80x94(CR42)nxe2x80x94C(G2)(R4)xe2x80x94(CR42)sxe2x80x94; and xe2x80x94Oxe2x80x94CH2xe2x80x94. Most preferably, Y is selected from the group consisting of xe2x80x94CH2xe2x80x94Oxe2x80x94; xe2x80x94CH2xe2x80x94NHxe2x80x94; xe2x80x94Sxe2x80x94; xe2x80x94NHxe2x80x94; xe2x80x94(CR42)nxe2x80x94S(O)pxe2x80x94(5-membered heteroaryl)-(CR42)sxe2x80x94; and xe2x80x94Oxe2x80x94CH2xe2x80x94.
In the ring at the left side of the structure (I), A, D, B, and E are preferably CH, and L is N or CH, with the proviso that when L is N, any substituents G3 are preferably monovalent, and when L is CH then any substituents G3 are preferably divalent.
The substituents G3 are preferably selected from the group consisting of monovalent moieties lower alkyl; xe2x80x94NR3COR6; xe2x80x94OR6; xe2x80x94SR6; xe2x80x94S(O)R6; xe2x80x94S(O)2R6; xe2x80x94CO2R6; xe2x80x94CON(R6)2; xe2x80x94S(O)2N(R6)2; xe2x80x94CN; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted heteroarylalkyl; optionally substituted heteroaryloxy; xe2x80x94S(O)p(optionally substituted heteroaryl); optionally substituted heteroarylalkyloxy; xe2x80x94S(O)p(optionally substituted heteroarylalkyl); and bivalent bridge of structure T2xe2x95x90T2xe2x80x94T3 wherein T2 represents N or CH. T3 is preferably S, O, CR42, or NR3.
Most preferably, G3 is selected from the group consisting of monovalent moieties lower alkyl; xe2x80x94NR3COR6; xe2x80x94CO2R6; xe2x80x94CON(R6)2; xe2x80x94S(O)2N(R6)2; and bivalent bridge of structure T2xe2x95x90T2xe2x80x94T3 wherein T2 represents N or CH. Most preferably T3 is S, O, CH2, or NR3.
Most preferably, the subscript q, which represents the number of substituents G3, is 1.
Ring J is preferably a phenyl ring, and subscript qxe2x80x2 representing the number of substituents G4 on the phenyl ring, is preferably 0, 1, 2, or 3. Subscript qxe2x80x2 is most preferably 1, or 2.
G4 moieties are preferably selected from the group consisting of xe2x80x94N(R6)2; xe2x80x94NR3COR6; halogen; alkyl; halogen-substituted alkyl; hydroxy-substituted alkyl; carboxy-substituted alkyl; lower alkoxycarbonyl-substituted alkyl; amino-substituted alkylamino; N-lower alkylamino-substituted alkylamino; N,N-di-lower alkylamino-substituted alkylamino; N-lower alkanoylamino-substituted alkylamino; hydroxy-substituted alkylamino; carboxy-substituted alkylamino; lower alkoxycarbonyl-substituted alkylamino; phenyl-lower alkoxycarbonyl-substituted alkylamino; xe2x80x94OR6; xe2x80x94SR6; xe2x80x94S(O)R6; xe2x80x94S(O)2R6; halogenated lower alkoxy; halogenated lower alkylthio; halogenated lower alkylsulfonyl; xe2x80x94OCOR6; xe2x80x94COR6; xe2x80x94CO2R6; xe2x80x94CON(R6)2; xe2x80x94CH2OR3; xe2x80x94NO2; xe2x80x94CN; optionally substituted heteroarylalkyl; optionally substituted heteroaryloxy; xe2x80x94S(O)p(optionally substituted heteroaryl); optionally substituted heteroarylalkyloxy; xe2x80x94S(O)p(optionally substituted heteroarylalkyl); as well as fused ring-forming bridges attached to and connecting adjacent positions of the phenyl ring, said bridges having the structures: 
xe2x80x83wherein each T2 independently represents N, or CH; T3 represents S, or O; and binding to the phenyl ring is achieved via terminal atoms T2 and T3; 
xe2x80x83wherein each T2 independently represents N, CH, or CG4xe2x80x2; with the proviso that a maximum of two bridge atoms T2 may be N; and binding to the phenyl ring is achieved via terminal atoms T2; and 
xe2x80x83wherein each T5, and T6 independently represents O, S, or CH2; and binding to ring J is achieved via terminal atoms T5; with the provisos that:
i) a bridge comprising T5 and T6 atoms may contain a maximum of two heteroatoms O, S, or N; and
ii) in a bridge comprising T5 and T6 atoms, when one T5 group and one T6 group are O atoms, or two T6 groups are O atoms, said O atoms are separated by at least one carbon atom.
Alkyl groups which constitute all or part of a G4 moiety are preferably lower alkyl.
When G4 is an alkyl group located on ring J adjacent to the linkage xe2x80x94(CR42)pxe2x80x94, and X is NR3 wherein R3 is an alkyl substituent, then G4 and the alkyl substituent R3 on X may be joined to form a bridge of structure xe2x80x94(CH2)pxe2x80x2 wherein pxe2x80x2 is preferably 2 or 3, with the proviso that the sum of p and pxe2x80x2 is 2 or 3, resulting in formation of a nitrogen-containing ring of 5 or 6 members. Most preferably, the sum of p and pxe2x80x2 is 2, resulting in formation of a 5-membered ring.
Most preferably, in G1, G2, G3, and G4, when two groups R6 are each alkyl and located on the same N atom they may be linked by a bond, an O, an S, or NR3 to form a N-containing heterocycle of 5-6 ring atoms.
Preferably, when an aryl, heteroaryl, or heterocyclyl ring is optionally substituted, that ring may bear up to 2 substituents which are independently selected from the group consisting of amino, mono-loweralkyl-substituted amino, di-loweralkyl-substituted amino, lower alkanoylamino, halogeno, lower alkyl, halogenated lower alkyl, hydroxy, lower alkoxy, lower alkylthio, halogenated lower alkoxy, halogenated lower alkylthio, xe2x80x94CH2OR3, nitro, and cyano.
The method of the invention is intended to be employed for treatment of VEGF-mediated conditions in both humans and other mammals.
The compounds may be administered orally, dermally, parenterally, by injection, by inhalation or spray, or sublingually, rectally or vaginally in dosage unit formulations. The term xe2x80x98administered by injectionxe2x80x99 includes intravenous, intraarticular, intramuscular, subcutaneous and parenteral injections, as well as use of infusion techniques. Dermal administration may include topical application or transdermal administration. One or more compounds may be present in association with one or more non-toxic pharmaceutically acceptable carriers and if desired, other active ingredients.
Compositions intended for oral use may be prepared according to any suitable method known to the art for the manufacture of pharmaceutical compositions. Such compositions may contain one or more agents selected from the group consisting of diluents, sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide palatable preparations.
Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which arc suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; and binding agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. These compounds may also be prepared in solid, rapidly released form.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
Aqueous suspensions containing the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions may also be used. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropyl-methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, sweetening, flavoring and coloring agents, may also be present.
The compounds may also be in the form of non-aqueous liquid formulations, e.g., oily suspensions which may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or peanut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
The compounds may also be administered in the form of suppositories for rectal or vaginal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal or vaginal temperature and will therefore melt in the rectum or vagina to release the drug. Such materials include cocoa butter and polyethylene glycols.
Compounds of the invention may also be administered transdermally using methods known to those skilled in the art (see, for example: Chien; xe2x80x9cTransdermal Controlled Systemic Medicationsxe2x80x9d; Marcel Dekker, Inc.; 1987. Lipp et al. WO 94/04157 Mar. 3, 1994). For example, a solution or suspension of a compound of Formula I in a suitable volatile solvent optionally containing penetration enhancing agents can be combined with additional additives known to those skilled in the art, such as matrix materials and bacteriocides. After sterilization, the resulting mixture can be formulated following known procedures into dosage forms. In addition, on treatment with emulsifying agents and water, a solution or suspension of a compound of Formula I may be formulated into a lotion or salve.
Suitable solvents for processing transdermal delivery systems are known to those skilled in the art, and include lower alcohols such as ethanol or isopropyl alcohol, lower ketones such as acetone, lower carboxylic acid esters such as ethyl acetate, polar ethers such as tetrahydrofuran, lower hydrocarbons such as hexane, cyclohexane or benzene, or halogenated hydrocarbons such as dichloromethane, chloroform, trichlorotrifluoroethane, or trichlorofluoroethane. Suitable solvents may also include mixtures one or more materials selected from lower alcohols, lower ketones, lower carboxylic acid esters, polar ethers, lower hydrocarbons, halogenated hydrocarbons.
Suitable penetration enhancing materials for transdermal delivery systems are known to those skilled in the art, and include, for example, monohydroxy or polyhydroxy alcohols such as ethanol, propylene glycol or benzyl alcohol, saturated or unsaturated C8-C18 fatty alcohols such as lauryl alcohol or cetyl alcohol, saturated or unsaturated C8-C18 fatty acids such as stearic acid, saturated or unsaturated fatty esters with up to 24 carbons such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl isobutyl tert-butyl or monoglycerin esters of acetic acid, capronic acid, lauric acid, myristinic acid, stearic acid, or palmitic acid, or diesters of saturated or unsaturated dicarboxylic acids with a total of up to 24 carbons such as diisopropyl adipate, diisobutyl adipate, diisopropyl sebacate, diisopropyl maleate, or diisopropyl fumarate. Additional penetration enhancing materials include phosphatidyl derivatives such as lecithin or cephalin, terpenes, amides, ketones, ureas and their derivatives, and ethers such as dimethyl isosorbid and diethyleneglycol monoethyl ether. Suitable penetration enhancing formulations may also include mixtures one or more materials selected from monohydroxy or polyhydroxy alcohols, saturated or unsaturated C8-C18 fatty alcohols, saturated or unsaturated C8-C18 fatty acids, saturated or unsaturated fatty esters with up to 24 carbons, diesters of saturated or unsaturated dicarboxylic acids with a total of up to 24 carbons, phosphatidyl derivatives, terpenes, amides, ketones, ureas and their derivatives, and ethers.
Suitable binding materials for transdermal delivery systems are known to those skilled in the art and include polyacrylates, silicones, polyurethanes, block polymers, styrene-butadiene coploymers, and natural and synthetic rubbers. Cellulose ethers, derivatized polyethylenes, and silicates may also be used as matrix components. Additional additives, such as viscous resins or oils may be added to increase the viscosity of the matrix.
For all regimens of use disclosed herein for compounds of Formula I, the daily oral dosage regimen will preferably be from 0.01 to 200 mg/Kg of total body weight. The daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/Kg of total body weight. The daily rectal dosage regimen will preferably be from 0.01 to 200 mg/Kg of total body weight. The daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/Kg of total body weight. The daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily. The transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/Kg. The daily inhalation dosage regimen will preferably be from 0.01 to 10 mg/Kg of total body weight.
It will be appreciated by those skilled in the art that the particular method of administration will depend on a variety of factors, all of which are considered routinely when administering therapeutics. It will also be understood, however, that the specific dose level for any given patient will depend upon a variety of factors, including, but not limited to the activity of the specific compound employed, the age of the patient, the body weight of the patient, the general health of the patient, the gender of the patient, the diet of the patient, time of administration, route of administration, rate of excretion, drug combinations, and the severity of the condition undergoing therapy. It will be further appreciated by one skilled in the art that the optimal course of treatment, i.e., the mode of treatment and the daily number of doses of a compound of Formula I or a pharmaceutically acceptable salt thereof given for a defined number of days, can be ascertained by those skilled in the art using conventional treatment tests.
The compounds of the invention may be prepared by use of known chemical reactions and procedures. Nevertheless, the following general preparative methods are presented to aid the reader in synthesizing the KDR inhibitors, with more detailed particular examples being presented below in the experimental section describing the working examples.
All variable groups of these methods are as described in the generic description if they are not specifically defined below. When a variable group or substituent with a given symbol (i.e. R3, R4, R6, G1, G2, G3, or G4) is used more than once in a given structure, it is to be understood that each of these groups or substituents may be independently varied within the range of definitions for that symbol. As defined above, the compounds of the invention contain ring units each of which may independently bear between 0 and 5 substituents G1, G3, or G4, which are not defined as H. By contrast, it is to be noted that in the general method schemes below, the G1, G3, or G4 substituents are used as if their definition includes H, to show where such G1, G3, or G4 substituents may exist in the structures, and for ease in drawing. No change in the definition of G1, G3, or G4 is intended by this non-standard usage, however. Thus, only for purposes of the general method schemes below, G1, G3, or G4 may be H in addition to the moieties set forth in the definitions of G1, G3, or G4. The ultimate compounds contain 0 to 5 non-hydrogen groups G1, G3, or G4.
Within these general methods the variable M is equivalent to the moiety 
in which each variable group or substituent is allowed to independently vary within the limits defined earlier for that symbol.
Within these general methods the variable Q1 is equivalent to the moiety 
in which L is N and each other variable group or substituent is allowed to independently vary within the limits defined earlier for that symbol.
Within these general methods the variable Q2 is equivalent to the moiety 
in which each variable group or substituent is allowed to independently vary within the limits defined earlier for that symbol.
It is recognized that compounds of the invention with each claimed optional functional group cannot be prepared with each of the below-listed methods. Within the scope of each method optional substituents are used which are stable to the reaction conditions, or the functional groups which may participate in the reactions are present in protected form where necessary, and the removal of such protective groups is completed at appropriate stages by methods well known to those skilled in the art.
The compounds of formula I-A in which X, M, and Q2 are defined as above, Y is xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94CH2xe2x80x94Sxe2x80x94, xe2x80x94CH2xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94NHxe2x80x94, and R1 and R2 together with the carbons to which they are attached form a fused 5-membered ring aromatic heterocycle, hal is halogen (Cl, Br, F, or I but preferably Cl, Br or F) are conveniently prepared according to a reaction sequence as shown in Method A. Thus, a heterocycle of formula II in which R is lower alkyl can be made by one skilled in the art according to the corresponding published procedures in the reference table. In the cases of thiophene-2,3-dicarboxylic acid (table entry 1) and pyrazole-3,4-dicarboxylic acid (table entry 10), the carboxylic acids are converted to methyl or ethyl esters by treatment with the corresponding alcohol and catalytic mineral acid (typically sulfuric acid) at reflux. The diester of formula II is treated with hydrazine hydrate to furnish intermediate III (for specific reaction conditions see Robba, M.; Le Guen, Y. Bull. Soc. Chem. Fr. 1970 12 4317). Compound III is treated with a halogenating agent such as phosphorous oxychloride, phosphorous oxybromide, phosphorous pentabromide, or phosphorous pentachloride to yield dihalo intermediate IV. The dichloro or dibromo intermediates can be converted to the difluoro intermediate (when desired) by reaction with hydrogen fluoride. By using iodo reagents such as potassium iodide or tetrabutylammonium iodide in subsequent steps, the iodo intermediate is formed in the reaction mixtures without being isolated as a pure substance. Dihalo intermediate IV is treated with a nucleophile of formula V in refluxing alcohol or other suitable solvent such as tetrahydrofuran (THF), dimethoxyethane (DME), dimethylformamide (DMF), dimethylsulfoxide (DMSO), or the like to furnish the intermediate of formula VI. Such condensations can also be done in a melt free of solvent and can be catalyzed by acids such as HCl or bases such as triethylamine or 1,8-diazobicyclo[5.4.0]undec-7-ene (DBU). The compound of formula VI is reacted with compounds of formula VII in a suitable aprotic solvent such as DMSO, DMF or solvent free often with a basic catalyst such as DBU or CsCO4, or a crown ether such as 18-crown-6 at temperatures usually between room temperature and reflux to furnish invention compound of formula I-A. It is understood that the nature of the starting materials will dictate the choice of suitable solvents, catalyst (if used) and temperature by one skilled in the art. Intermediates of formula V and VII are often commercial or are conveniently prepared by methods well known to those skilled in the art. For example see Martin, I., et al. Acta. Chem. Scand. 1995 49 230 for the preparation of VII in which Y is xe2x80x94CH2Oxe2x80x94 and Q2 is 4-pyridyl substituted by a 2-aminocarbonyl group (2-CONH2). 
The compounds of formula I-B in which M, X, and Q2 are as defined above and Y is xe2x80x94CH2Oxe2x80x94, xe2x80x94CH2xe2x80x94Sxe2x80x94, xe2x80x94CH2xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94NHxe2x80x94 are conveniently prepared as shown in Method B. According to a procedure described in the literature (Tomisawa and Wang, Chem. Pharm. Bull., 21, 1973, 2607, 2612), isocarbostyril VIII is reacted with PBr5 in a melt to form 1,4-dibromoisoquinoline IX. Intermediate IX is treated with a nucleophile of formula V in refluxing alcohol to furnish intermediate of formula X. Such condensations can also be done in a melt free of solvent and can be catalyzed by acids such as HCl or bases such as triethylamine or 1,8-diazobicyclo[5.4.0]undec-7-ene (DBU). The compound of formula X is reacted with compounds of formula VII in a suitable aprotic solvent such as DMSO, DMF or solvent free often with a basic catalyst such as DBU or CsCO4 at elevated temperatures to furnish invention compound of formula I-B. This method is most useful when Y is xe2x80x94CH2xe2x80x94Sxe2x80x94 or xe2x80x94Sxe2x80x94. 
The compounds of formula I-C in which M, X, R1, R2, m and Q2 are defined as above are conveniently prepared according by a reaction sequence as shown in method C. In this method m is preferably 0 and R1 and R2 together with the carbons to which they are attached form a fused benzene or fused 5-member ring aromatic heterocycle. Starting material XI is either commercial or is prepared by one skilled in the art as shown in the reference table below. Starting material XI is reacted with urea or ammonia, usually at elevated temperature and pressure (in the case of ammonia), to form imide XII. The imide is reacted with an aldehyde XIII in acetic acid and piperidine at reflux to yield intermediate XIV. Reaction of XIV with sodium borohydride in methanol or other suitable solvents according to the general procedure described by I. W. Elliott and Y. Takekoshi (J. Heterocyclic Chem. 1976 13, 597) yields intermediate XV. Treatment of XV with a suitable halogenating agent such as POCl3, POBr3, PCl5, PBr5 or thionyl chloride yields halo intermediate XVI which is reacted with nucleophile of formula V in refluxing alcohol to furnish invention compound of formula I-C. Such condensations can also be done in a melt free of solvent and can be catalyzed by acids such as HCl or bases such as triethylamine or 1,8-diazobicyclo[5.4.0]undec-7-ene (DBU). Alternatively, reagent V can be condensed with intermediate XV be heating the two components with P2O5 in a melt to yield invention compound of structure I-C. This last method is especially effective when X is an amine linker. 
The compounds of formula I-D-1 in which R1, R2, R6, M, X, Y, G3 and Z are defined as above and q is 0 or 1 are conveniently prepared via a reaction sequence as shown in Method D. Thus, pyridine substituted pyridazines or pyridines (I-D-1) are functionalized into substituted 2-aminocarbonyl pyridines of formula (I-D-2) by the use of formamides (XVII) in the presence of hydrogen peroxide and iron salts, according to a procedure described in the literature (Minisci et al., Tetrahedron, 1985, 41, 4157). This method works best when R1 and R2 together constitute a fused aromatic heterocycle or fused aromatic carbocycle. In those cases that Z is CH and R1 and R2 do not form a fused aromatic, an isomeric side product in which Z is CCONHR6 can be formed and, if so formed, is removed from the desired product by chromatography. 
The compounds of formula I-E-1 and I-E-2 in which R1, R2, R6, M, X, Y, G3, and Z are defined as above, q is 0 or 1, and R3 is lower alkyl are conveniently prepared via a reaction sequence as shown in Method E. Thus, pyridine substituted pyridazines or pyridines (I-D-1) are functionalized into substituted 2-alkoxycarbonyl pyridines of formula (I-E-1) by the use of monoalkyloxalates (XVIII) in the presence of S2O8xe2x88x922, acid and catalytic amounts of AgNO3, according to a procedure described in the literature (Coppa, F. et al., Tetrahedron Letters, 1992, 33 (21), 3057). Compounds of formula I-E-1 in which R3 is H are then formed by hydrolysis of the ester with a base such as sodium hydroxide in methanol/water. Compounds of formula I-E-2 in which the R6 groups are independently defined as above, but especially including those compounds in which neither R6 is H, are conveniently prepared from the acid (I-E-1, R3=H) by treatment with amine XIX in the presence of a coupling agent such as DCC (dicyclohexylcarbodiimide). This method works best when R1 and R2 together constitute a fused aromatic heterocycle or fused aromatic carbocycle. In those cases that Z is CH and R1 and R2 do not form a fused aromatic, an isomeric side product in which Z is CCO2R3 can be formed in the first step and, if so formed, is removed from the desired product by chromatography. 
The compounds of formula I-F in which M, Q2 and X are defined as above, m is an integer of 1-5, and R1 and R2 together with the carbons to which they are attached form a fused 5-membered ring aromatic heterocycle can be prepared via a reaction sequence as shown in method F. The readily available heterocyclylcarboxylic acid starting material XX is reacted with butyl lithium followed by dimethylformamide to yield the aldehyde with structure XXI. Reaction of XXI with hydrazine yields pyridazinone XXII. Treatment of XXII with a suitable halogenating agent such as POCl3, POBr3, PCl5, PBr5 or thionyl chloride yields a halo intermediate which is reacted with nucleophile of formula V in refluxing alcohol to furnish intermediate compound of formula XXIII. Such condensations can also be done in a melt free of solvent and can be catalyzed by acids such as HCl or bases such as triethylamine or 1,8-diazobicyclo[5.4.0]undec-7-ene (DBU). Alternatively, reagent V can be condensed with intermediate XXII be heating the two components with P2O5 in a melt to yield XXII. This last method is especially effective when X is an amine linker. Formation and alkylation of the Reissert compound XXIII with halide XXIV is done as described by the general method of F. D. Popp, Heterocycles, 1980, 14, 1033 to yield the intermediate of structure XXV. Treatment of XXV with base then yields invention compound I-F. 
The compounds of formula I-G in which M, Q2 and X are defined as above, m is an integer of 1-4, and R1 and R2 together with the carbons to which they are attached form a fused 5-membered ring aromatic heterocycle can be prepared via a reaction sequence as shown in method G. Aldehyde XXI, from method F, can be reduced with sodium borohydride to yield a hyroxyacid which is lactonized using methods well known to those skilled in the art such as with toluenesulfonyl chloride to yield lactone XXVI. Condensation of intermediate XXVI with aldehyde XIII in the presence of a base such as sodium methoxide usually in a solvent such as methanol under reflux yields an intermediate of structure XXVII. Reaction of XXVII with hydrazine or preferably with hydrazine hydrate at a temperature of 100-150xc2x0 C. leads to an intermediate of structure XXVIII. Conversion of intermediate XXVIII to invention compound of structure I-G is done by methods as described in method C by using XXVIII rather than XV. 
The compounds of formula I-H in which the R1, R2, M, X, R6; q and G3 are defined as above are conveniently prepared via a reaction sequence as shown in Method H. Thus the methods described in Martin, I; Anvelt, J.; Vares, L.; Kuchn, I.; Claesson, A. Acta Chem. Scand. 1995, 49, 230-232 or those of methods D or E above by substituting readily available pyridine-4-carboxylic ester XXX for I-D-1 are used to convert XXX into XXXI. Reduction of the ester as described by Martin, et al. above is next done with a mild reducing agent such as NaBH4 such that the amide substituent is left unchanged to yield alcohol XXXII. This alcohol is then heated with a base such as DBU or CsCO4 with halopyridazine VI from method A under anhydrous conditions to yield the invention compound with formula I-H. 
Invention compounds having formula I-I in which the R1, R2, M, X, R6, q, and G3 are defined as above and W is a bond or xe2x80x94CH2xe2x80x94 are conveniently prepared via a reaction sequence as shown in Method I. This method is especially useful when q is 1 and XXXIII is 4-chloropyridine. Alternatively, other 4-halopyridines such as 4-fluoropyridine or 4-bromopyridine can be used in this process. Thus readily available 4-halopyridines XXXIII are converted to intermediates of formula XXXIV by using the general procedures of methods D or E above by substituting the 4-halopyridine for I-D-1. Reaction of XXXIV with either potassium or sodium hydrogen sulfide yields a thiol having formula XXXV. Alternatively, the alcohol function of intermediate XXXII from method H is converted to a leaving group by reaction with methanesulfonyl chloride and a suitable base such as triethylamine in the cold such that polymeric material formation is minimized and the resultant intermediate is reacted with either potassium or sodium hydrogen sulfide to yield a thiol having formula XXXVI. Either thiol have formula XXXV or formula XXXVI is reacted with intermediate VI from method A and a suitable base such as diisopropylethylamine or CsCO4 in DMF or other suitable anhydrous solvent or in the absence of solvent to yield I-D-9. 
Invention compounds such as those having formula I-J-1 or I-J-2 in which the R1, R2, M, X, W, and G3 are defined as above and having a sulfoxide or sulfone within the structure are conveniently prepared via a reaction sequence as shown in Method J. Reaction of compounds of this invention that contain a thioether group either as part of a substituent G1, G3, or G4or as part of Y as shown in the representative structure I-I from Method I can be converted to the invention compounds with a sulfoxide moiety such as I-J-1 by treatment with one equivalent of m-chloroperbenzoic acid in methylene chloride or chloroform (MCPBA, Synth. Commun., 26, 10, 1913-1920, 1996) or by treatment with sodium periodate in methanol/water at between 0xc2x0 C. and room temperature (J. Org. Chem., 58, 25, 6996-7000, 1993). The expected side products consisting of mixtures of various N oxides and the sulfone I-J-2 can be removed by chromatography. The sulfone I-J-2 is obtained by the use of an additional equivalent of MCPBA or preferably by use of potassium permanganate in acetic acid/water (Eur. J. Med. Chem. Ther., 21, 1, 5-8, 1986) or by use of hydrogen peroxide in acetic acid (Chem. Heterocycl. Compd., 15, 1085-1088, 1979). In those cases that unwanted N oxides become a significant product, they can be converted back to the desired sulfoxides or sulfones by hydrogenation in ethanol/acetic acid with palladium on carbon catalysts (Yaklugaku Zasshi, 69, 545-548, 1949, Chem. Abstr. 1950, 4474). 
Invention compounds having formula I-K in which the R1, R2, M, X, and Q1 are defined as above are conveniently prepared via a reaction sequence as shown in Method K. One skilled in the art prepares starting materials of structure XXXVII by methods known in the literature. For example XXXVII wherein R1 and R2 together with the carbons to which they are attached form a 2,3-substituted thiophene, furan, pyrrole, cyclopentadienyl, oxazole or thiazole are prepared using the general chemistry given in J. Org. Chem., 1981, 46, 211 and hydrolizing the initially formed tert-butyl ester with trifluoroacetic acid. The pyrazole starting material can be prepared by reacting 2-oxo-3-pentyn-1,5-dioic acid (J. Chem. Phys. 1974, 60, 1597) with diazomethane. The starting material wherein R1 and R2 together with the carbons to which they are attached form a phenyl are prepared by the methods of Cymerman-Craig et al., Aust. J. Chem. 1956, 9, 222, 225. Compounds of formula XXXVII in which R1 and R2 are lower alkyl are conveniently prepared according to procedures given in patent CH 482415 (Chem. Abstr. 120261u, 1970). The crude diacid of formula XXXVII is subsequently treated with hydrazine to furnish pyridazinone XXXVIII (for specific reaction conditions see Vaughn, W. R.; Baird, S. L. J. Am. Chem. Soc. 1946 68 1314). Pyridazinone XXXVIII is treated with a chlorinating agent such as phosphorous oxychloride to yield an intermediate dichloro species which undergoes hydrolysis upon aqueous workup to furnish chloropyridazine XXXIX. Chloro acid XXXIX is treated with a nucleophile of formula V in the presence of a base such as sodium hydride in a solvent such as DMF or in the absence of a solvent. The resultant acid XXXX is reduced with a reducing agent such as BH3.THF according to the procedure of Tilley, J. W.; Coffen D. L. Schaer, B. H.; Lind, J. J. Org. Chem. 1987 52 2469. Product alcohol XXXXI is reacted with a base and optionally substituted 4-halo-pridyl, optionally substituted 4-halo-pyrimidyl or optionally substituted 4-halo-pyridazyl (XXXXII) to furnish invention compound of formula I-K (for specific reaction conditions see Barlow, J. J.; Block, M. H.; Hudson, J. A.; Leach, A.; Longridge, J. L.; Main, B. g.; Nicholson, S. J. Org. Chem. 1992 57 5158). 
Invention compounds having formula I-L in which the R1, R2, M, X, and Q1 are defined as above are conveniently prepared via a reaction sequence as shown in Method L. Thus alcohol of formula XXXXI from method K is reacted with methanesulfonyl chloride in the presence of a suitable base followed by potassium or sodium hydrogen sulfide to yield thiol XXXXIII. The thiol is then reacted with 4-halopyridine XXXXII from method K in the presence of a suitable base such as triethylamine to yield invention compound I-K. Alternatively, XXXXI is converted to halo intermediate of formula XXXXIV by methods well known to those skilled in the art and the halide is reacted with thiol XXXXV to yield I-K. Intermediate XXXXIV can also be converted to intermediate XXXXIII by treatment with KHS or NaHS. Reagents XXXXV are either commercially available such as 4-mercaptopyridine or can be prepared by one skilled in the art such as by method I above. 